The brain's histamine system is involved in numerous important regulatory functions that are critical to emotional and physical well-being, including contributing to the control of mood, cognitive functioning (including memory and attention processes), arousal and sleep patterns (including diurnal and seasonal variation), appetite, neuroendocrine responses to stress and other stimuli, and brain reward processing systems. Histamine is a neurotransmitter in the central nervous system that is involved in the regulation of sleep, appetite, cognition, and, perhaps, mood. Agents such as the first generation antihistamines that block histamine type 1 (H1) receptors in the brain are known to cause sedation and increased appetite/weight gain.
Certain subtypes of depression have been associated with decreased function of the hypothalamic-pituitary-adrenal (HPA) axis as evidenced by low cortisol and/or decreased CRH and ACTH levels. Histamine has been shown to enhance the secretion of ACTH and cortisol. In addition, histamine has been shown to increase the synthesis of corticotropin releasing hormone (CRH) mRNA in rat hypothalamus. Conversely, blocking the H1 receptor has been shown to diminish the ACTH response to stress (Knigge, Willems et al. 1999). Studies performed by the present inventors and colleagues have also shown that in rats betahistine increases the cortisol response to stress, and counteracts the decrease in cortisol observed after dexamethasone administration. Moreover, a recent study reported that the MAOI antidepressant phenelzine also increases cortisol levels in mice (Kier et al., 2005), which is relevant to the treatment of atypical depression as MAOIs are superior to other antidepressants classes such as tricyclic antidepressants, which have been reported to decrease cortisol secretion. In summary, both the H3 antagonist betahistine and MAOIs, which are the most proven antidepressants in atypical depression (i.e. hypocortisolemic depression), exhibit the property of increasing HPA axis activity in animal models.
MAOI antidepressants have been shown to decrease the metabolism of histamine, and thereby may increase histamine levels in the brain. Conversely, TCAs, which are less effective than MAOIs in atypical depression have significant antihistaminic activity. Moreover, histamine enhancing compounds, particularly H3 receptor antagonists, have been reported to inhibit monoamine oxidase activity in animal studies.
Evidence suggests that tricyclic antidepressants (TCAs) and possibly serotonin reuptake inhibitors (SRIs) have decreased efficacy in treating atypical depression as these agents have been reported to be less effective than monoamine oxidase inhibitors (MAOI) in double-blind controlled trials in this population. Moreover, evidence suggests that depressed patients who exhibit atypical features are more prone to relapse with SRIs than patients who do not have atypical features. MAOIs, on the other hand, have been shown to be effective, but are generally not well tolerated, and are associated with potentially severe drug and dietary interactions. Given this possible reduced response rate with some antidepressants in atypical depression, there is a need to find alternative treatments that are as effective as MAOIs, but better tolerated.
In addition, studies in humans and animals have suggested a link between brain histamine function and several other disorders relating to brain reward systems and internal regulatory control of behavior. These mechanisms are implicated in such aberrant human behaviors such as substance abuse and over-eating. Alcoholism is one of the world's most costly drug abuse problems and, with the exception of nicotine, is more costly to most countries than all other drug use problems combined. Overcoming alcoholism through behavioral modification based treatments alone is extremely difficult and has a high rate of recidivism.
Obesity is another disorder that has at least some basis in faulty regulatory mechanisms. Obesity adversely affects all body organs and bodily functions, especially the heart, blood vessels, joints and blood sugar metabolism. As a person's level of obesity increases, so does their risk for disease. It is estimated that up to 30 percent of all Americans are obese, and the economic cost in medical costs, reduced productivity and shortened life spans, as well as the toll on human dignity, is astronomical and probably realistically immeasurable. Certain subtypes of obesity may be particularly benefited by new approaches to treatment based on targeting internal regulatory mechanisms.
Hence, there is a continuing need for pharmaceutical approaches to complement behavioral approaches to the treatment of certain human disorders by targeting the underlying physiological mechanisms which may manifest as substance abuse or weight management difficulties.